PROJECT SUMMARY/ABSTRACT The emergence of the immune system as a key regulator of mood identifies novel opportunities for the treatment of debilitating mental health disorders such as major depression. Yet, while converging data impli- cate excessive proinflammatory cascades and T cell overactivation in the development and persistence of MDD, the relationship between MDD and B lymphocytes has not been well studied leaving a gap in our knowledge regarding the immune theory of depression. Several findings highlight key roles for B cells in the response to stress and modulating mood, including preliminary data implicating B cell deficiency with a mala- daptive response to acute forced swim stress, a response that was ameliorated with immune modulation. Thus, B cells may play a critical, but not well delineated, role on the stress response and mood. The exciting potential of this burgeoning field has shaped the applicant?s long-term research goal: to elucidate mechanisms by which the immune system regulates neurobiological substrates that control brain function. As B cell impacts on the brain are not well known, the objective of this proposal is to define the mechanisms by which B cells modulate the stress response and to support the applicant to become an independent, R01- funded investigator in the mental health field with expertise in immune regulation of brain function and behav- ior. The crucial next step in this research is to systematically identify mechanisms by which B cells control mood. The central hypothesis of this proposal is that the immunoregulatory action of B cells maintains resili- ence from stress via secretion of the immunosuppressive cytokine, interleukin-10. To test this promising hy- pothesis, the role of the B cell on the stress response and associated neural substrates of mood will be verified using in vivo B cell depletion (Aim 1). Next, using mice that lack regulatory but not other B cells, or mice whose B cells lack cannot secrete interleukin-10, the potential for immunomodulatory mechanisms of B cells to influ- ence the adaptation of a stress-induced maladaptive behavioral pattern and display other abnormalities seen in MDD will be assessed (Aim 2). Finally, B accumulation and release of interleukin-10, at central nervous system target sites will be evaluated (Aim 3). Completion of these studies and training will support the development of the applicant?s independent research program by providing the evidential basis for continued exploration of this topic and enhance competitiveness for the successful acquisition of extramural funding. Indeed, data generat- ed here will provide insight into mechanisms involved in B cell control of mood and the resilient versus suscep- tible response to acute and chronic stress. In doing so, this proposal will advance the applicant?s career goal to provide additional insight into the mechanisms underlying the resilience and susceptibility to stressors, to posi- tively impact the mental health field as a productive scientist, to help improve clinical practice with the discov- ery of new therapeutic targets and approaches, and ultimately, to ease the burden of mood disorders.